Lactones and process of making same



Patented Oct. 16, 1945 g UNITED- STATES PATENT OFFI LACTONE S AND PROCESS OF MAKING SAME Leopold Ruzicka tzurich, Switzerland, assignor to ibal- Pharmaceutical Products; Incorporated, Summit, N. J a, corporation of New Jersey No-Drawing; Application March 8, 1943, Serial No. 478,480. InSwitzerland March 16, 1942 Claims. (01. zoo-239.5),

It has'been found that lactones can be obtained and a method of preparation for theparent; me;- when saturated or unsaturated compounds of the terials: 1 general formula: 0 I Q A H I (wherein R1 and R2 each stand for a member of the group consisting of hydrogen and organic radicals, e. g. aliphatic, cycIo-aliphatic or aroc RP matic, which maybe connected by means of a.

bridge, X represents halogen, Y1, Y2 and Y: each v stand for a member of the group consisting of 5 hydrogen and alkyl, and'n has one of the values 0 and 1), are treated with metals in the presence Rr- H-----0 of an inert solvent, and the condensation products obtained subjected, if desired, to dehydration 1,; and/or hydrolysis. This is aReformatsky reac- 0 *1 7 tion, being a reaction between the carbonyl group, R1G=0Y1 Rr-O' Q as. at the left in the above formula, and the halo H 0 rest, l ester group as at the right. 1

The starting compounds are thus aor p-halo- \Q,/ RFOH 0 gen fatty acids, e. g. chlorine, bromine or iodine (Where 71:0) derivatives of acetic acid, propionic acid, butyric acids, valeric acids, esterified with -ketols or R1, R2 Y1 t Y3 and a g t already a-hydroxy-aldehydes; They can easily be pretimed significance p d i an already known y, p e y As products of the condensation reaction, comthe reaction of diazoketoneswith thefatty acids pounds are obtained t 5 6 membered, tmentioned, or by esterification of the ketols or mated and hydroxylated c t ringnr 1; hydroxy-aldehy With e halogenated fatty urated lactone ring. From the compounds-with acids. Suitable diazoketones are, for example, a, 6 membered hydroxylated lactone rir gi gon],

(where n=1) diazo-acetone; 3diazo-butane-2-one, diazoacetopoundstwith a, 7,601 B-double bond canbe obnzen or y 10 an py d a tained by dehydration, in addition to compounds nzene or -cy 10h X n 3'-di 0 0- ywith the fi,'y-unsaturated lactone ringillustrated droxy-ot, 3-diethy1 stilbene, 4'-diazoacet04-hyf yfifi d a 11y- The condensation is carried out in a known r xy ab y ydr a amanner by means of metals suchas zinc ormag p oi', diazo-epi-camphor, A '-3- ydr0Xy- ,-d nesium, in a suitable inert solvent such as" ben azo pregnene-20-one, diam-pr esterone, h -3'- zene, toluene, dioxane or ether. Partial dehyyd Y- edration generally already takes place during the EY Q -C -0 condensation reaction. Mixtures are thus ob- 21-diaZ0 D e e I- 0'- e, -d aZ0-p tained which can be worked up without or after e- Y Y- il separation. The condensation product is then a -p n n -on fu h r th sp dsubjected, if desired, to a known method of dehying esters or ethers, and derivatives substituted r ti n, for which procedure treatmentwith fatty (for examp hydroxylated) n e 12 Or 14 acid anhydrides, distillation-or sublimation under posit on of the'steroid nucleus. As the compounds reduced pressure, if required after mixing with menliloned Show, the p t comp nd y substances which lower surface tension, such as tain the esterified ketol group for example as a aluminum oxide, silica gel, active charcoal, substituent attached directly to a carbon ring or fuller arth, o with anhydrous salts such as to the sideachain of a carbon ring. copper sulphate, has proved to be particularly The following formulas illustrate the course of suitable. The product of the reaction is subthe reaction in thelight of present day knowledge, jected to the usual means of separation; e. g; fractional crystallization or chromatographic adsorption, in order to isolate the pure compound.

The following examples illustrate the invention but are not to be regarded as limiting it in any way:

Example 1 2.0 g A -3eacetoxy-2l-bromoacetoxy-pregnene-20-on'e of M. Pt. 137-438 C. and specific ro tation ldlb=+225 (in chloroform) andhaving the formula: C e0 Bron,

on, 00 (\A/ o CHtC00-\/ ,7

(prepared for example from A -3-acetoxy-21-di- 9 azo-pregnene--one by causing it to react-with bromoacetic acid) are dissolved in 20 cc.:of absolute benzene and the solution boiled under reflux with 1.56 g. of zinc foil', until the zinc is ala most dissolved. In order to start up the reaction, the addition of a few, drops of bromoacetic acid is sometimes advantageous. 'The benzene solution is cautiously concentrated down, a little absolute ethyl alcohol added to the residue and the solution filtered off from the zinc mud. The alcoholic solution is poured into ice-cold dilute hydrochloric acid and the precipitated product dissolved in ether. The alcoholic ether layer is washed with plenty of water; the main quantity of the reaction product separates out as a white powder and is filtered off. This product, which is comparatively slightly soluble in ether can be purified by crystallization from glacial acetic acid or absolute alcohol. It then melts at 239 C. and is the A 40 3-acetoxy-20,2l-dihydroxy-norcholenic acid lactone of the formula 0H cm- OH: I l

0H, 00 \J \O/ "'GHmOO -V so Dehydration to the corresponding unsaturated lactone is easily carried out by heating to 240 C. in vacuo. Also on -longer boiling with acetic anhydride, the unsaturated lactone, namely the A '-3-acetoxy 21 hydroxy norcholadienic acid lactone, M. Pt. 173-174 C., is obtained. By

' w Thereaction runs a similar course if ketol ester of other halogen fatty acids, e. g. a or p -bromopropionic acid,- are used.

- Ercrnple 2 I 7 1 '4 g.? 'or'; A5 3-acetoxy-2lbromoacctoxy-p e nene-20-one and 6 g. of zinc foil are dried in a high vacuum. 40 cc. of dioxane are then added. The reaction mixture is cautiously warmed and heated for a short time under reflux. 2 cc. of absolute alcohol are then added, and the whole boiled for 1 hour on a water-bath. 30 cc. of the solution are then distilled off, the contents of the flask dissolved in cc. of absolute alcohol and filtered ofi from the zinc residue. The clear filtrate is concentrated down in vacuo to about 40 cc. and ether and dilute hydrochloric acid added in a separating funne1.- After shaking up for a short time, a yellowish precipitate separates out from the ether solution in' the form of fairly coarse granules. It is filtered off, washed first with ether until the yellow colour disappears and then with dilute hydrochloric acid and water, and finally dried in vacuo. This reaction product is then heated with acetic anhydride in pyridine for 2 hours to 60 C., whereupon the solution obtained is concentrated down and the residue chromatographed using a column of 60a. of aluminium oxide prepared with benzene. On elution with ether the lactone of A -3-acetoxy-2l-hydroxy-nor-choladienicacid, M. Pt. 170-172 C., is obtained. Finally the lactone of A -3-acetoxy- 20,2l-dihydroxy-nor-cholenic acid described in Example 1 can be'eluted with acetone.

Example 3 omooo 5.9 g. of this bromoacetoxy ketone and 9.5- g. ofactivated zinc foil are sharply dried. 80 cc. of dried benzene are then added and about one third of the solvent distilled oil to dry the apparatus. There is then heated under reflux, if necessary with the addition of a few drops of bromoacetic acid, until the reaction starts. After the reaction has subsided the mixture is boiled for a short time under reflux, diluted with cc. of absolute alcoholand filtered ofi from the unchanged zinc. 40 cc. of concentrated hydrochloric acid are added to the filtrate to complete lactonization, and the mixture warmed for a short time on a water-bath. After cooling, it is diluted in water and the product of the reaction dissolved in ether. On concentrating the ether solution down to a small volume, the greater part of the reaction mixture crystallizes out. On filtering off by suction, a product is obtained which is negative in Legals test. It is mainly fl-iA -ti-hydroxy nor cholenyl -(23) J-flfydihydroxy-n-butyric acid-v-lactone or its 3-monoacetate.

This crude product is boiled for several hours under reflux with 150 cc. of acetic anhydride. The reaction' solution is evaporated down in vacuo, the residue boiled up, with a little methyl alcohol, and the mixture again evaporated down.

assent CH3 CH3; CHa

It gives. a positive action to Legals test. and an absorption: maximum at about 220 mu. (log=4.I) If, instead of a bromoacetic acid ester, a bromo propioriic acid ester isused for the manufacture off the parent material, the corresponding buten'olide, methylated; in the. a-positi'on EM; Pt. 21%218" C2, Ea1n=- 43',8' (in CHC13)] is obtained: The acetateof' this" compound melts at 184-185" C. and has a specific rotation of Eu]D"j-"-41.8. a-hal'ogen derivatives of. higher fatty'acids'give also the corresponding a-alkylat ed butenQlides. If, on the other hand, fl halogen fatty'acid derivates are used, pentenolides are obtained; I v

If the reaction" is started from A -3-acetoxy- 25-bromoacetoxy-27-nor-cholestene-24-0ne (obtained by causing A -3-acetoxy-cholenic acid chloride to react with diazoethane and subsequently boiling" with bromoacetic acid), analogous products are obtained which have a methyl group in the 'y-position.

Example 4 I 2 g. of A -3 acetoxy 235-bromacetoxy norcholene-22-oneof the formula:

QHa CH4 i--cH-oo BTGH:

(prepared, for example, from A -K-acetoXy-ZS- diazo-nor-cholene-22 one, M; Pt. 260- 6?" (7., by reaction'with bromoacetic acid). are'dissolved' in 30 cc. ofabsolute benzeneand'treated with-4L0 g. of zinc-copper. Reaction soon sets in spontaneously; and after it has subsided, the mixture is heated for a short time under reflux, and then diluted with methyl alcohol. The unchanged zinc is then filtered off, the filtrate concentrated down and decomposed with aqueous hydrochloric acid. The solution obtained is boiled up for a short time and the product of the reaction dissolved in ether, after it has been allowed to cool.

CEa

After the ether solution has been evaporated down, the residue is boiled for afew hours with acetic anhydride. The excess anhydrid'e is evaporated. off in vacuo; when the crude A "-B[ A 3-- acetoxy pregnenyl-(ZOi-l -butenolide of the formula a 1 7 separated chromatographically.

is obtained. This is then purified chromatographically and converted into the A -B- [M -3- hydroXy-pregnenyl- (20) l-butenolide by saponification.

Example 5 1 g.:. of 3-hydroxy 2l-i bromoacetoxyepregnane 20 one. (obtained by-treatin'g- M dium-pregnanc- 3-ol-20-one, M. Pt. 174-178P'GL,'with bromoa'cetic acid) is rapidly dried and made to react with 1 g. of zinc filings in benzene. solution. The mixture is then diluted with alcohol, filtered offhot from. theunchanged zinc and the filtrate poured into 2N hydrochloric acid. The solvent is distilled off in steam and the residue dissolved in ethyl acetate. After the solvent has been evaporated off, the reaction product isacetylated with= pyrie dine-aceticanhydride, warming moderately- The product of acylation is worked up as ,us ualand The benzene ether eluates contain thejA q 3-acetoxy-21-hydroxy n0r-cholenic; acid lactone,

which melts at. 1664167 0. o n pcziyst lli tion from alcohol, gives a strongly positive reaction to Legals test and has an ultraviolet absorption, typical. of n p-unsaturated lactones (A maximum=220m,u). By acid saponification the l l-desoxy-digitoxigenin (lactone of the A -3,2l-dihydroxy-nor-cholenic acid), M. Pt. 225-227" C., is obtained. p

The ether-acetone eluates contain the lactone of" 3-acetoxy 20;2l dihydroxy-norcholanic acid, M. Pt. 204-207 6:, which is" boiled with acetic anhydricle to{ eliminate water; The acetate" of the l'actone of A -3,21-dihydroxy nor-'cholenic acid (acetate of l desoxy digitoxigenin), M. Pti 166'-16'7 C., thus'obtained can be saponifiedin acid solution as described". i

' Example 6 3'- diazoaceto-4 acetoxy- B-diethyl-dihydro stilbene, which canbe. prepared in any analogous way to the corresponding stilbene com-pound (Nature 1941 page 595) is converted by reaction with. bromoacetic. acid. into the corresponding ketolester of the formula:

1.0 g. of this bromoaceto-ketoneis dissolvedin 10 cc; of absolute Benzene and 750mg. ofpbwdered zinc-copperadded; The reaction is assisted by'boilingunderreflux until the greater part of the zinc-copper" is dissolved. The benzene is then cautiously evaporated'ofl' in vacuo, the residue dissolved in absolute alcoho-Ljand theundis solved material" separated off by filtration. The alcoholic solution is warmed fora short time with 2 cc. of concentrated hydrochloric acid' andthe reactiongproduct then precipitated by the add'i tion' ofplenty of water. After filtering oil by suction and washing with water, the product of the reaction is directly treated with acetic anhydride and pyridine. After evaporating oil the excess reagent in vacuo, th 3'-A""-butenolide of the 4-acetoxy 1,5 diethyl-dihydrostilbene is mainly on chromatography of the residue. I has the formula In addition the '3'-fl,'y-dihydroxy-n-ebutyric acidy-lactone of the4-acetoxy-a,,s-diethyl-dihydrostilbene of the formula: v a

is obtained. By acid saponification the corre- 'sponding 4hydroxy-compounds can be obtained from these two products.

What I claim is: V

' 1. A process for the manufacture of 'lactones,

which comprises subjecting to the Reformatsky reaction a compound of the formula Rr-CH wherein R1-CO represents an acyl radical free from substituents which interfere with the Reformatsky reaction, R2 represents a member of the group consisting of hydrogen and organic radicals, the bond between an R2 radical and the adjacent carbon atom being a carbon-to-carbon bond, X represents halogen, each of Y1, Y2 and Y3 wherein R1--CO represents an acyl radical free from substituents which interfere with the Reformatsky reaction, R2 represents a member of the group consisting of hydrogen and organic radicals, the bond between an R2 radical and the adjacent carbon atom being a carbon-to-carbon bond, X represents halogen, each of Y1, Y2 and Y3 stands for a member of the group consisting of hydrogen and alkyl, and n has one of the values 0 and 1, by reacting the said compound in an inert solvent medium with a metal in whose presence a carbonyl compound undergoesthe-Reformatslry reaction whereby ring closure takes .place and a lactone is formed, completing the reaction with the aid of a mineral acid whereby the said metal is split off in salt form from the lactone; and then subjecting the resultant product to a dehydrating treatment. 3. A process for the manufacture oflactones, which comprises subjecting to thesReformats reaction a compound of the formula A wherein R1 CO represents an acyl radical free from substituents which interfere with the Reiormatsky reaction, R2 representsa member of the group consisting of hydrogen and organic radicals, the bond between an R: radical and the adjacent carbon atom being a carbon-to-carbon bond, X represents halogen, each of Y Y2 .and Y: stands, for a memberrof the group consisting of hydrogen and alkyl, and n has one of the values 0 and 1, by reacting the said compound in an inert solvent medium with a metal in whose. presence a carbonyl compound undergoes the Reformatsky reaction, whereby ring closure takes place and-a lactone is formed, completing the reaction with the aid of a mineral acid whereby the said metal is split off in salt form fromth'e lactone and then subjecting the resultant product to ahydrolyzing treatment. I M v 4. A process forfthe manufacture of lactones, which comprises subjecting to the Reformatsky reaction a compound of the formula wherein Ri-CO represents an acyl radical free from substituents which interfere with the Reformatsky reaction, R2 represents a member of the group consisting of hydrogen and, organic radicals the bond between an R: radical and the adjacent carbon atom being a carbon-to-carbon bond, X represents halogen, each of Y1, Y2 and Y3 stands for a member of the group consisting of hydrogen and alkyl, and n has one of the values 0 and 1, by reacting the said compound in an inert solvent medium with a metal in whose presence a carbonyl compound undergoes the Reformatsky reaction, whereby ring closure takes place and a lactone is formed, completing the reaction with the aid of amineral acid whereby the saidmetal is split off in salt form fromthe lactone,'and subjecting the resultant productto a dehydrating and then to a hydrolyzing treatment.

5. A process for the manufacture of lactones, which comprises subjecting to the Reformatsky reaction a compound of the formula 1 I Y: 7 X-rCH C CO radicals, the bond between an R2 radical and the adjacent carbon atom being a carbon-to-carbon bond, X represents halogen, each of Y1, Y2 and Y3 stands for a member of the group consisting of hydrogen and alkyl, and n has one of the values 0 and 1, by reacting the said compound in an inert solvent medium with a metal in whose presence a carbonyl compound undergoes the Reformatsky reaction, whereby ring closure takes place and a lactone is formed, and completing the reaction with the aid of a mineral acid whereby the said metal is split 01f in salt form from the lactone.

LEOPOLD RUZICKA. 

